The overall goal of this project is to take an innovative approach to develop cell therapeutic agents from human umbilical cord blood-derived hematopoietic stem cells (UCB-HSC) to treat acute kidney injury (AKI). Acute kidney injury not only has a high morbidity and mortality rate but often leads to chronic kidney disease. At the present time, there is no specific treatment for AKI. Once the kidney fails, treatment of chronic kidney disease costs 20% Medicare expenditure. New and more effective treatments, such as stem cell-based therapy, will have significant clinical and financial impact. We have shown that mouse bone marrow HSC can be reprogrammed into cells expressing renal developmental genes after 1 week of treatment with cytokines and nephrogenic factors in vitro. Further treatment of the cells with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances reprogramming from 6% to 38%. Injection of the reprogrammed cells into mice with renal ischemic injury accelerates kidney structural and functional recovery. To begin to translate these findings clinically, we propose to reprogram human UCB- HSC and test their therapeutic effect in mouse models of AKI. Umbilical cord blood contains higher concentrations of CD34+ stem and progenitor cells. The cells can be isolated easily without risk to the donors. The UTSW-affiliated Parkland Memorial Hospital delivers about 47 infants a day, which ensures an abundant supply for cell isolation. Using a similar approach for the mouse bone marrow HSC, CD34+ cells from human umbilical cord blood will be treated in vitro with cytokines, nephrogenic factors and a HDAC inhibitor TSA to induce hematopoietic-to-renal conversion. The induced cells will be characterized for the expression of a panel of renal developmental genes, and their ability to differentiate into epithelial cells and form tubular structures (Aim 1). Furthermore, the induced cells will be transplanted into mice with acute ischemia-reperfusion injury to test whether they accelerate renal functional and structural recovery. The mechanisms of renal protection by direct cell replacement into the repairing tubules and/or paracrine effect to decrease epithelial and endothelial injury and increase intrinsic renal cell regeneration will be investigated (Aim 2). This project may represent the first step toward translation of stem cell biology to the bedside. We are confident that with our experience and dedication, we will be able to complete the studies in Aim 1 in the first 9 months and the studies in Aim 2 in the next 15 months. PUBLIC HEALTH RELEVANCE: Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at the present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop cell therapeutic agents from human umbilical cord blood-derived stem cells to treat acute kidney injury.